Method of preparing 7-dehydrosterols and esters



Patented Dec. 18, 1951 UNITED PATENT OFFICE 2,579,295 Mn'rnon OFPREPARINGjY-DEHYDKO- 'STEROLS E'STERS Jan Anne Keven-ting Buisman, iEin'dhoven, Netherlandsya ssigmoratoHartford National. Bank Jami TrustCompanygflartform(101111., as. trustee 1 N'o nrawing. Application April 28; 1947, Serial No. 744;;531h1111flh Netherlands June 5, 1946 to a method of prepar is iolahhs, o zoo-397.2)

ing 'Z-deh-ydrosterols and esters, morelparticularlyeof preparing 'Z-dehydrocholesterol, a compound. which is essential as a primary body for vitamin fig g f by radlatmg It 'e riu e cos. of dimethylaniline, 1 ccLof, e01- IHS known r h ..m referred hdme and 50 mgms. of 7-ahydroxycho1esterolto from a 7-hydroxysterolester by splitting-01f i n P 5 p mtmgen the substituent at the"7-pos'ition. 'This involved 't l i g h a The i re the'problem that thesubstituent at the 3rd posilm p m i w h 15 9 f Q tion would not also be split-oft, so that products, m bmled half an m m a would be obtained which cannot serve as progen mQS pF ex the content of steromhat vltamin v canhev precipitated by means of digitonine in the It has'hitherto been necessary to solve this: reactmn'prodmt 6 r n d and the problemby'utilizing 'l-hydroxysterol's esterifledfatrsfiQF-PKQ? f o ifi 3 t the position? (vide for exampleAmerica-n Pat-#3 sterol'dlgltmtme, Obtamed a qe by ent- Specification 2,098,984 and. J; Am. :Chem! spectmgmphlc means" Th 1 748M510- Soc. 64 1177 (1942)). i ho e t l n qu ly In contradistinction thereto the present inmgmsof -B' 3 y e tero1-3-benvention provides a means enabling, in general, mate of P 1 the splitting-off of the substituent at the posiof comdme and 2 of d1n}ethY1a m1me are tion 7, without splitting-off the substituent at the heated together to a 1011 for 5 mmutes a Introposition 3, by the action of a halide or oxyhalide g atmosphelie; Subsequently, is of an inorganic acid dissolved in a tertiary amine, f c by bmlmg Wlth 81100110110 ye, also in a as a dehydrating means, on a 7-hydroxysterol-3- mtrogen atmosphere (for half an AS 111 monoester' Example I, the content of digitonisable sterol and For carrying t the invention use may be made the content of 'l dehydrocholesterol are deterof 7-hydroxysterols, of i which, for example, nl mined. A yield of sterol of 45% and a content 01 the hydroxyl group is esterified at the positi 3, '1-dehydrocholesterol of 76% are found, so that the for example means of acetic acid benzo ic 0f 7-dehydr0ch0lester01 is of theoacid, stearic acid. retically le.

As examples of dehydrating means suitable for After boiling f r 3 minutes a mixture of carrying out the invention, solutions of, for ex- 50 mgmS. 0 y y r 0a ample, thionyl chloride, sulphuryl chloride, 50 mgms. of phosphorus oxychloride and 3 cos. of phosphorus oxychloride, phosphorus tribromide, ,P in a nitrogen a p e, the yield of and so forth in tertiary amines, for example, pyri- 7-olehydrocholesterol s ained, as in EX- dine, pyridine ho -nologues chinoline alkylqtgd ample I and is found (20 be 3% Of the theoretical aniline bases and so forth, or mixtures thereof yield. may be instanced. The yield of '7-dehydrostero1- After boiling or minutes a mixture of ester depends on the nature of the halide or oxy- 40 50 mgms- 0f Y Y I-3- e ate, halide, the nature of the amine, the durationof 50 sof phosphor-us oxychloride and 3 cos. of direaction, the temperature of reaction, and so m h nil n 1 f h h r i l yield is obforth. v tained.

The action oi the halide (oxyhalide) mixture V-After boiling for 30minutes a mixture of 50 ensues at an increased temperature, forv "exmgms. of '7-a-hydr0xych01e r 1- nzoate, ample, at the boiling point of the amine eo'nmems. of ph phorus poxly hl ride and a mixture cerned. The duration of action depends on-the of 2 cos. of dimethylaniline and 1 cc. of collidine, halide-amine mixture used, neither excessively 5% of the theoretically possible yield is obshort nor excessively long heating leading to the tained. optimum yield due to excessively short time of 50 VI, 51 mgms. of 7-a hydroxycholesterol-3-benreaction and decomposition of the ldehydro- 0 56 mgmsf thi0ny1 c o 2 CC of d sterolestei; formed respectively. methylaniline and 1 ccrof collidine are boiled The reaction is advantageously performed to for 5 minutes in nitrogen. The yield of '7-dehythe exclusion of oxygen, in order to obviate dedrocholesterol is largely 1%.

55 VII. 40 mgms. of '7-e-hydroxycholesterol-3- composition of the 7-dehydrosterolester, for exampiem amatmosphere o'f'nitrogeh, hyurogeh or the'l'ike. v

- trample: I. A mixture of 50 mgms. oi phospho-rus oxy- 4 cos. of dimethylaniline and 1 cc. of collidine' -are boiled for two hours in a nitrogen atmosphere.

It is found that the yield of 7-dehydr0cholesterol is 44%.

IX. 24 mgms. of 7-a-hydroxycholesterol-3- stearate, 50 mgms. of phosphorus oxychloride',

1 cc. of collidine and 2 cos. of dimethylaniline are boiled for 5 minutes under nitrogen. Thus a yield of 7-dehydrocholesterol of 15% is .ob'-.

tained.

What I claim is: 1. A method of preparing a 'T-dehydrosterol monoester to the action of an inorganic acid, halide in a tertiary amine While heating the latter to a boiling temperature with the exc lu sion of oxygen whereby the hydroxyl group at the 7-p0sition is split off and a 7-dehydrosterol ester is formed. 4 I,

2. A method of preparing a 'Ldehydrosterol which comprises the steps of subjecting aI-hydroxysterol-3-monoesterto the action of an inorganicacid oxyhalide in a tertiary amine with the exclusion of oxygen while heating the latter to a boiling temperature whereby the hydroxyl group at the 7-pos ition is split off and a 7-de hy drosterol ester is vformed and saponifying the latter to form a ,7-dehydrosterol, 7 I

3. A method of preparing a 'l-dehydrosterol which comprises the stepsof subjecting a..7-hywhich -comprises subjecting a '7-hydroxysterol-3e-;

droxysterol-3-monoester to the action of phosphorous tribromide in a tertiary amine with the exclusion of oxygen while heating the latter to a boiling temperature whereby the hydroxyl group is split ofi at the 7-position and a '7-dehydrosterol ester formed and saponifying the latter to form a 7-dehydrosterol.

4. A method of preparing a 'I-dehydrosterol which comprises the steps of subjecting a 7-hy- .l0

droxysterol-3-monoester to the action of phosphorous oxychloride in a tertiary amine while heating the latter to a boiling temperature with the exclusion of oxygen whereby the hydroxyl groupis split oflat the 7-position and a 7-dehydrosterol ester is formed and saponifying the latter to form a 'l-clehydrosterol.

-' 5. A method ofpreparing a 'I-dehydrosterol which comprises the steps of subjecting a 7-hydroxysterol-3-monoester .to the action of thionyl chloride in a tertiary amine while heating the latter to a boiling temperature with the exclusion roxyg'en, whereby the hydrfoxyl" group is-s plit of! at the'Fpo'sitio'n'and a 7-dehydros'terol ester is formed and saponifyin'g the latter to form a '7-dehydroste'rol.

JAN ANNEKEVERLING BUISMAN.

REFERENCES CITED The following references are of record in the file of this patent: r

UNITED'STATES PATIENTS.

Number Name Date I 2,098,984 Windaus Nov; 16,1937 2,350,485 'Arund'ale'- June 6, 1944 2,395,232

Meuly Feb. 19, 1946 

1. A METHOD OF PREPARING A 7-DEHYDROSTEROL WHICH COMPRISES SUBJECTING A 7-HYDROXYSTEROL-3MONOESTER TO THE ACTION OF AN INORGANIC ACID HALIDE IN A TERTIARY AMINE WHILE HEATING THE LATTER TO A BOILING TEMPERATURE WITH THE EXCLUSION OF OXYGEN WHEREBY THE HYDROXYL GROUP AT THE 7-POSITION IS SPLIT OFF AND A 7-DEHYDROSTEROL ESTER IS FORMED. 